2. Academic Validation
  3. Discovery of new LXRβ agonists as glioblastoma inhibitors

Discovery of new LXRβ agonists as glioblastoma inhibitors

  • Eur J Med Chem. 2020 May 15;194:112240. doi: 10.1016/j.ejmech.2020.112240.
Hao Chen 1,  Ziyang Chen 1,  Zizhen Zhang 1,  Yali Li 1,  Shushu Zhang 1,  Fuqiang Jiang 1,  Junkang Wei 1,  Peng Ding 1,  Huihao Zhou 2,  Qiong Gu 3,  Jun Xu 4
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Research Center for Drug Discovery at School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Research Center for Drug Discovery at School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China. Electronic address: [email protected].
  • 3 Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Research Center for Drug Discovery at School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China. Electronic address: [email protected].
  • 4 Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Research Center for Drug Discovery at School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China. Electronic address: [email protected].
PMID: 32248003 DOI: 10.1016/j.ejmech.2020.112240
Abstract

Discovery and optimization of selective liver X receptor β (LXRβ) agonists are challenging due to the high homology of LXRα and LXRβ in the ligand-binding domain. There is only one different residue (Val versus Ile) at the ligand-binding pocket of LXRs. With machine learning methods, we identified pan LXR agonists with a novel scaffold (spiro[pyrrolidine-3,3'-oxindole]). Then, we figured out the mechanism of LXR isoform selectivity from co-crystal structures. Based on the mechanism and the new scaffold, LXRβ selective agonists were designed and synthesized. This led to the discovery of LXRβ agonists 4-7rr, 4-13 and 4-13rr with IC50 values ranging from 1.78 to 6.36 μM against glioblastoma in vitro. Treatment with 50 mg/kg/day of 4-13 for 15 days significantly reduced tumor growth using an in vivo xenograft glioblastoma model.

Keywords

Glioblastoma inhibitor; Nuclear receptor; Spiro[pyrrolidine-3,3′-oxindole]; Structure-based drug design.

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